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IL12-mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression.
- Source :
-
PloS one [PLoS One] 2013 Jul 02; Vol. 8 (7), pp. e67748. Date of Electronic Publication: 2013 Jul 02 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Recombinant adenoassociated viral vectors (rAAV) have proven to be excellent candidates for gene therapy clinical applications. Recent results showed that cellular immunity to AAV represents a major challenge facing the clinical use of systemic administration of these vectors. Interestingly, no preclinical animal model has previously fully reproduced the clinical findings. The aim of the present work was to enhance the T cell immune response against AAV capsid in mice by the administration of a rAAV expressing the immunostimulatory cytokine IL-12. Our results indicate that although IL-12 expression enhanced the AAV capsid-specific immune response it failed to eliminate transduced hepatocytes and long-term expression was achieved. We found that AAV-mediated transgene expression is altered by IL-12-induced liver inflammation. However, IL-12 expression has no effect over preexisting AAV-mediated transgene expression. IL-12 down-regulates AAV mediated transgene expression via induction of IFN-γ production by NK and T cells, but without altering the transduction efficiency measured by viral genomes. Our results indicate that liver inflammation affects the formation of transcriptionally active AAV vector genomes through an unknown mechanism that can be avoided by the use of DNA-demethylating or anti-inflammatory agents.
- Subjects :
- Animals
Capsid immunology
Dependovirus genetics
Female
Genetic Therapy methods
Genetic Vectors immunology
Hepatocytes pathology
Inflammation genetics
Inflammation immunology
Inflammation pathology
Interferon-gamma genetics
Interferon-gamma immunology
Interleukin-12 genetics
Killer Cells, Natural cytology
Killer Cells, Natural immunology
Liver pathology
Mice
Mice, Inbred C57BL
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
T-Lymphocytes cytology
T-Lymphocytes immunology
Transgenes immunology
Dependovirus immunology
Gene Expression immunology
Hepatocytes immunology
Interleukin-12 immunology
Liver immunology
Transcription, Genetic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23844082
- Full Text :
- https://doi.org/10.1371/journal.pone.0067748